The modification of the natural pigmentation of the skin is a desirable fact for several reasons for many people in America, Asia or Europe. Some of the reasons for modifying the natural color of the skin include the search for lighter skin as a model of beauty, and the elimination or attenuation of spots on the skin such as freckles or lentigines.
Dysfunctions in the melanin production mechanism due to external aggressions, exposure to UV radiation, inflammations, hormonal disturbances, pregnancy (melasma), photoageing or ageing induce hyperpigmentation and the occurrence of brown spots, particularly in the form of freckles or solar or senile lentigines.
Skin and hair color is due to a series of cell processes carried out by melanocytes. Melanocytes are cells of neuroectodermal origin that are bound by dendrites to the cells of the basal layer of the epidermis at a proportion of approximately one melanocyte for every ten basal cells, regardless of race. The main function of the melanocyte is to synthesize the melanin through cellular and hormonal interaction.
Melanin is a dark pigment found in the skin, hair, eyes and certain nerve cells and protects the body from the harmful effects of ultraviolet radiation. There are two types of melanin pigments, eumelanin and pheomelanin. Eumelanin is black, while pheomelanin has a lighter color, between reddish and yellow. Skin and hair tone is determined by the proportion of one or another type of pigment. These pigments accumulate in melanosomes in the melanocyte cytoplasm and are carried by the melanosomes to dendrites where they are injected in the basal cell cytoplasm. A homogenous melanin distribution in the basal layer of the epidermis thus occurs, giving uniform pigmentation of the skin [Hearing V. J. (1999) “Biochemical control of melanogenesis and melanosomal organization” J. Invest. Dermatol. Symp. Proc. 4:24-28]. In the same manner, hair color depends on the amount and the quality of the melanin located in the cortex of the hair stalk. Said melanin is produced by the melanocytes located at the base of the root and depends on hereditary, hormonal, nutritional factors, etc. Over the years, the amount of melanin of the hair decreases due to the reduction of melanocyte activity, justifying the whitening of hair (gray hair).
Therefore, human skin and hair color is directly related to the size, configuration, type, color and distribution of these melanosomes. Melanosomes are formed by, among others, melanin and melanoprotein, which is a product of the interaction with the enzyme tyrosinase. Tyrosinase is a glycoprotein located in the membrane of melanosomes and catalyzes to first steps in formation of pigment, i.e. the ortho-hydroxylation of the amino acid tyrosine which produces L-dopa and the oxidation of the latter to give dopaquinone [Hearing V. G. and Tsukamoto K. (1991) “Enzymatic control of pigmentation in mammals” FASEB J. 5:2902-2909].
Depending on the levels of cysteine and/or of the compounds with sulfhydryl groups inside the melanosomes, dopaquinone reacts in a eumelanogenesis or pheomelanogenesis process. If cysteine levels are low, dopaquinone is converted into eumelanin by autoxidation processes. If cysteine levels are high, dopaquinone combines with cysteine to form cysteinyldopa, which is subsequently modified to generate pheomelanin.
Melanin pigmentation of the skin can be divided into several causal components: 1) cutaneous melanin generated according to genetic programs in the absence of exposure to ultraviolet rays (constitutive skin color) and 2) immediate and delayed tanning reactions induced by direct exposure of the skin to UV radiation (facultative skin color). The changes in facultative color are a result of the interaction between sunlight, hormones and the tanning capacity, the latter being dependent on the genetic constitution of each individual.
All human beings, regardless of their skin and their hair color, have approximately the same amount of epidermal melanocytes in a given anatomical area. Ethnic color differences are due to differences in the properties of melanosomes and not to the amount of melanocytes. It must also be taken into consideration that the melanocyte distribution is not uniform in the skin and that there is approximately twice the number of melanocytes in the exposed areas than in the non-exposed areas.
Apparent changes in skin color occur throughout a person's lifetime and thus, for example, skin spots appear in the skin of the face, neck, neck-line and hands of older people which are clear signs of ageing [Piérard G. E., Piérard-Franchimont C., Laso Dosal F., Ben Mosbah T., Arrese Estrada J., Rurangirwa A., Dowlati A. and Vardar M. (1991) “Pigmentary changes in skin senescence” J. Appl. Cosmetol. 9:57-63]. This change in the number of age-dependent epidermal melanocytes has been quantified in a reduction of up to 10% in non-exposed areas of the skin per decade of life. The reduction in the number of melanocytes is lower in exposed areas due to the stimulating effect of UV radiation in the melanocyte population. Furthermore, continued overexposure to UV radiation causes accelerated ageing in the skin, known as photoageing, which is characterized by the onset at a much earlier age of the signs of skin ageing, including the onset of spots in those areas of the skin overexposed to UV radiation [Stefanaki C., Stratigos A. and Katsambas A. (2005) “Topical retinoids in the treatment of photoaging” J. Cosmet. Dermatol. 4:130-134].
It frequently occurs that the melanin density in the melanocytes is greater in an area of an individual's skin than in the surrounding areas and as a result the individual has a darker color in the affected area than in the rest. These areas are known as hyperpigmentation areas. Some of the causes of hyperpigmentation include hormonal alterations, melasma, lentigo, piebaldism, Addison's disease, hypersensitivity to ultraviolet radiation due to agents favoring the action of radiation (phototoxins), or hyperpigmentation resulting from an inflammatory lesion. Spots associated to acne, eczemas, scars or depilation belong to this latter type of hyperpigmentation and these spots can last even several years.
There are also areas of an individual's skin having lower melanin densities than in the surrounding areas. Said type of hypopigmented spots are known as vitiligo [Dooley T. P. (1994) “Recent advances in cutaneous melanoma oncogenesis research” Onco. Res. 6:1-9; Benmaman O. and Sanchez J. L. (1988) “Treatment and camouflaging of pigmentary disorders” Clin. Dermatol. 6:50-61; Schallreuter K. U. (1997) “Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis” J. Invest. Dermatol. 2:37-40]. Though it would be desirable to be able to restore pigmentation in the areas affected by vitiligo with topical application, it has been shown that this approach is extremely difficult in most subjects suffering vitiligo. An alternative to phototherapy with UVA rays or to the use of cosmetic make-up of the affected area with dihydroxyacetone lotions [Benmaman O. and Sanchez J. L. (1988) “Treatment and camouflaging of pigmentary disorders.” Clin. Dermatol. 6:50-61] is the reduction of the degree of pigmentation of the non-affected surrounding skin to reduce the contrast between both areas.
Irregularities in pigmentation of the skin can also be caused by exposure to environmental factors. Exposure of the skin, especially Caucasian skin, to ultraviolet radiation, particularly UVB, promotes the synthesis of endogenous tyrosinase, resulting in an increase of melanogenesis and therefore in skin tanning. However, persistent exposure to UVB radiation can result in the formation of cancerous hyperpigmented lesions or melanomas [Dooley T. P. (1994) “Recent advances in cutaneous melanoma oncogenesis research” Onco. Res. 6:1-9] as well as in non-malignant hyperpigmented spots due to photoageing.
Furthermore, there is a market need consisting of depigmenting agents for lightening natural skin color due to the fact that a lighter skin color is perceived as more desirable for some dark-skinned people in different countries and races due to sociological or psychological reasons [Dooley T. P. (1997) “Is there room for a moderate level of regularity oversight?” in “Drug Discovery Approaches for Developing Cosmeceuticals: Advanced Skin Care and Cosmetic Products”, Ed. Hori W, Chapter 1.4, International Business Communications, Southborough, Mass., USA; Dooley T. P. (1997) “Topical skin depigmentation agents: Current products and discovery of novel inhibitors of melanogenesis” J. Dermatol. Treat. 8:275-279].
In the same manner, within the beauty standards established in most countries and races, facial hair in women (known as hirsutism) is not desirable, especially dark facial hair, nor is body hair desirable. Despite the fact that different technologies such as depilation or laser treatment allow eliminating facial or body hair in a relatively effective manner, said treatments are usually painful or expensive, so there is a need for depigmenting agents which allow simply and effectively lightening the color of facial and body hair.
To modify the degree of pigmentation, it is even possible to inhibit melanin distribution in the epidermal cell layers or to cause melanin degradation by means of melanogenesis inhibitors which interact with enzyme tyrosinase or with any other enzyme involved in melanogenesis.
There is a strong demand for depigmenting agents which allow restoring spots or freckles to a normal skin color and therefore allow reducing the signs of ageing and of photoageing. For many years, skin depigmentation or lightening was done using very strong products such as hydroquinones or derivatives thereof, particularly their ethers such as monomethyl ether and monoethyl ether. Though these compounds show certain efficacy, they have adverse effects due to their toxicity, even making them hazardous. Thus, hydroquinone, for example, is irritating and cytotoxic for melanocytes, causes irreversible hypopigmentation, subsequently increasing photosensitization in areas of the skin exposed to UV radiation and has shown indications of mutagenicity [Glatt H., Padykula R., Berchtold G. A., Ludewig G., Platt K. L., Klein J. and Oesch F. (1989) “Multiple activation pathways of benzene leading to products with varying genotoxic characteristics” Environ Health Perspect 82:81-89; Glatt H. R. (1990) “Endogenous mutagens derived from amino acids.” Mutat. Res. 238:235-243] and accordingly, its use is prohibited in some countries and legally limited in others to concentrations of less than 2%. Another widespread depigmenting agent is kojic acid and its family of derivatives. However, said compound is not problem-free since allergic reactions after continued use have been documented [Nakagawa M., Kawai K. and Kawai K. (1995) “Contact allergy to kojic acid in skin care products” Contact Dermatitis 42:9-13], and furthermore the compound is unstable in solution, making it difficult to manufacture compositions containing it.
Other rather aggressive chemical compounds that have been tested as depigmenting agents are peroxides, acids, mercury salts, formaldehyde or thiolated compounds. Many of these compounds have a rather pungent and/or unpleasant smell, rendering them unusable for marketing in cosmetic or pharmaceutical compositions.
Topical retinoids and corticosteroids have also been proposed as whitening agents, although they have failed to provide a favorable response. Arbutin and its derivatives are also used, though they are only marginal tyrosinase inhibitors and have little bioavailability. Other widely used depigmenting agents are vitamin C and its derivatives, such as ascorbyl-2-phosphate magnesium salt (MAP) or ascorbyl-2-phosphate sodium salt (NAP) for example, although they basically have the same instability drawbacks in formulations as those described for kojic acid.
Other recently proposed compositions use natural product extracts, some of which have been used as whitening agents for centuries in Asia or in Europe, such as lemon, orange, ginkgo, cucumber, geranium, bearberry, carob bean, cinnamon, marjoram, rosemary, clove, blackberry or licorice extracts. The variety of active ingredients in the extracts of these natural products and the possible allergic reactions of natural products occasionally limit the use of these natural agents.
The use of most whitening or depigmenting compounds whether for treating hyperpigmented areas or of areas next to hypopigmented areas, for aesthetic reasons to lighten the natural skin color, has a collateral effect of increasing the risk of damage due to UV radiation, since it decreases the amount of melanin produced by melanocytes. Melanin is the natural photoprotector of the skin, as it dissipates in the form of heat over 99.9% of absorbed UV radiation [Meredith P. and Riesz J. (2004) “Radiative Relaxation Quantum Yields for Synthetic Eumelanin” Photochem. Photobiol. 79:211-216]. This means that less than 0.1% of the absorbed radiation is able to generate free radicals, which are the agents causing direct and indirect damage to DNA and, therefore, of photoageing. The cosmetic and pharmaceutical sectors compensate for this deprotection inherent to the use of whitening or depigmenting agents by adding photoreactive substances or solar filters to their formulations. Solar filters protect the skin from UVB radiation, which can cause burns, and from UVA radiation, which causes long-term damage to the skin causing accelerated ageing or photoageing. Solar filters are classified into 1) chemical filters containing chemical compounds absorbing UV radiation and emitting it in the form of low-energy radiation that is not harmful for the skin, 2) physical filters containing opaque materials reflecting UV radiation or 3) biological filters preventing the formation of free radicals and enhance the cutaneous immunological system. However, many of these substances are potentially irritating, sensitizing or toxic, their use being regulated and even limited or prohibited in different countries. Therefore, there is a need to develop whitening or depigmenting compounds with intrinsic photoprotective efficacy which allows reducing the use of additional photoprotectors.
Thus there is a need to develop new, safer, more chemically stable molecules and/or molecules having greater efficacy than substances known in the state of the art for treating those conditions, disorders and/or pathologies of the skin, hair and/or nails in which a regulation or reduction of the amount of melanin produced by the melanocytes is desirable.
The applicant of the present invention has found that 6-substituted 7-methoxy-2,2-dimethylchromanes are capable of reducing the amount of melanin produced by the melanocytes by means of the inhibition of the enzyme tyrosinase and, in turn, to protect against damage caused by UV radiation.
In the state of the art, document EP 0655239 A1 discloses anticarcinogenic drugs containing 6,7-disubstituted 2,2-dialkylchromanes or 6,7-disubstituted 2,2-dialkylchromenes as anti-free radical agents.
Patent document JP 2001-002558 describes cosmetic compositions of 6,7-disubstituted 2,2-dialkylchromanes or 6,7-disubstituted 2,2-dialkylchromenes with hydroxy, methoxy or 2-trifluoroethoxy groups having a whitening effect and an effect of increasing the permeability of the epidermal barrier due to the fact that these compounds inhibit melanogenesis and sebaceous secretion in the skin.
Patent documents EP 1430879 A2, EP 1430933 A2 and EP 1336403 A1 describe the use of 6,7-disubstituted 2,2-dialkylchromanes or 6,7-disubstituted 2,2-dialkylchromenes with hydroxy, methoxy or 2-trifluoroethoxy groups in cosmetic deodorant or antiperspirant compositions, in compositions for treating hair loss and in compositions with anti-inflammatory activity, respectively.
Patent applications EP 1002533 A1 and EP 1430882 A2 describe cosmetic or dermatological compositions of 6,7-disubstituted 2,2-dimethylchromanes with hydroxy, methoxy or 2-trifluoroethoxy groups, alone or combined with other antioxidants, respectively. Patent documents EP 1634576 A1 and EP 1343465 A2 describe, among others, cosmetic compositions, 6-hydroxy-7-methoxy-2,2-dimethylchromane compositions (Lipochroman-6 marketed by Lipotec S.A.) or 6-hydroxy-7-methoxy-2,2-dimethylchromene combined with DNA-repair enzymes.
The use of Lipochroman-6 as an antioxidant agent inhibitor of lipid peroxidation in cosmetic or dermatological compositions is also known [Puig A. (2002) “Synthetic actives for cosmetic applications” Specialty Chemicals Magazine 2002, 22(10):16-17]. Lipochroman-6 also acts as an oxygen-reactive radical species scavenger [Sanvicens N., Gomez-Vicente V., Masip I., Messeguer A. and Cotter T. G. (2004) “Oxidative stress-induced apoptosis in retinal photoreceptor cells is mediated by calpains and caspases and blocked by the oxygen radical scavenger CR-6” J. Biol. Chem. 279(38):39268-39278] and inhibitor of tyrosine nitration by peroxynitrites [Cebrian J., Messeguer A., Facino R. M. and Garcia Anton J. M. (2005) “New anti-RNS and -RCS products for cosmetic treatment” Int. J. Cosm. Science 27(5):271-278], which are processes related to skin ageing.
Likewise, patent document EP 1267813 A2 describes Lipochroman-6 cosmetic compositions as an MMP-1 matrix metalloprotease inhibitor. Patent documents WO 01/82888 A1, WO 02/05778 A1 and WO 02/47655 A1 describe Lipochroman-6 compositions alone or combined with other compounds, wherein Lipochroman-6 is an NO-synthase inhibitor. Particularly patent document WO 01/82888 also describes the use of its compositions to inhibit melanogenesis induced by ultraviolet radiation and/or the treatment of hypermelanosis-type disorders.
None of the previously mentioned documents describes 6-substituted 7-methoxy-2,2-dimethylchromanes with an ester or thioester group with 3 to 24 carbon atoms (C3-C24), and which are chemically modified derivatives of 6-hydroxy-7-methoxy-2,2-dimethylchromane.
Only 6-heptyloxy-7-methoxy-2,2-dimethylchromene and 6-lauroyl-7-methoxy-2,2-dimethylchromene compounds obtained from 6-hydroxy-7-methoxy-2,2-dimethylchromene are known in the state of the art. However, the 6-heptyloxy-7-methoxy-2,2-dimethylchromane or 6-lauroyl-7-methoxy-2,2-dimethylchromane analogues are not known.
Therefore the synthesis of 6-substituted 7-methoxy-2,2-dimethylchromanes with an ester or thioester group with 3 to 24 carbon atoms (C3-C24) is an object of the present invention.
The applicant of the present invention has surprisingly found that these compounds also have greater depigmenting activity than the compounds known in the state of the art, and particularly greater than 6-substituted 7-methoxy-2,2-dimethylchromane compounds with hydroxy, methoxy or 2-trifluoroethoxy groups, with intrinsic photoprotective efficacy.
There is no indication in the state of the art of that esterification or thioesterification should increase the depigmenting efficacy, therefore a person skilled in the art could not deduce the nature of the modifications required in chromanes to enhance their whitening capacity.
Therefore, the present invention provides a novel solution to the existing needs and comprises the discovery of 6-substituted 7-methoxy-2,2-dimethylchromanes with an ester or thioester group with 3 to 24 carbon atoms (C3-C24) capable of treating those conditions, disorders and/or pathologies of the skin, hair and/or nails which require regulating the degree of pigmentation in a safer and more effective manner than the whitening compounds already known in the state of the art.